Patients with beta-thalassemia (Cooley's Anemia) continue to suffer from the sequelae of transfusion-induced iron overload due to the inadequacies of current iron-chelation therapy. Compliance with the use of s.c. desferrioxamine (DFO) continues to be a major problem despite convincing evidence that it markedly reduces morbidity and prolongs life. The full potential of iron-chelation therapy will not be realized until an orally-effective drug is available. We have been conducting metabolic iron balance studies comparing the effectiveness of deferiprone (1,2-dimethyl-3-hydroxypyrid-4-one, DMHP, L1) and N,N'- bis(o-hydroxybenzyl)ethylenediamine-N,N'-diacetic acid (HBED) with that of DFO. While neither of these oral agents has yet fulfilled its promise, it appears likely that both will play a significant role in iron chelation therapy. Our standard DFO regimen (60 mg/kg infused s.c. over 8 hours) placed all patients in net negative iron balance, where balance is the ratio of iron excreted to that received in the form of transfused red cells. DMHP (75 mg/kg p.o. divided t.i.d.) was 60 percent as effective as DFO, 7/13 patients being in net negative iron balance. When deferiprone and DFO were combined, an additive effect was observed in 5/6 patients, synergy in the sixth. 2,3-Dihydroxybenzoic acid (2,3-DHB), another orally effective iron chelator, also had an additive effect when combined with DFO. In both cases, an overall towards urinary iron excretion suggested to us that the bidentate ligand (deferiprone or 2,3-DHB) was accessing pools of iron unavailable to DFO (hexadentate) and was "shuttling" this iron to the hexadentate "sink." HBED (80 mg/kg p.o. divided t.i.d.) was less effective than deferiprone, all patients being in positive balance (mean 52 percent). When deferiprone and HBED were combined, synergy was observed in 2/2 patients, both now achieving negative balance where neither was in negative balance on deferiprone alone. These results further support our "iron shuttle" hypothesis. We suggest combining drugs as a new approach to iron chelation therapy, both to reduce side effects and increase efficacy. If both drugs can be given orally, there is truly a good chance of finding a suitable alternative to DFO. We will further explore this hypothesis using both the hypertransfused rat model of iron overload and clinical studies.